Roles of Adenosine Receptor (subtypes A₁ and A_2A) in Cuprizone-Induced Hippocampal Demyelination

Hippocampal demyelination in multiple sclerosis (MS) has been linked with cognitive deficits, however, patients could benefit from treatment that induces oligodendroglial cell function and promotes remyelination. We investigated the role of A₁ and A_2A adenosine receptors (AR) in regulating oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocyte (OL) in the demyelinated hippocampus using the cuprizone model of MS. Spatial learning and memory were assessed in wild type C57BL/6 mice (WT) or C57BL/6 mice with global deletion of A₁ (A₁AR-/-) or A_2A AR (A_2AAR-/-) fed standard or cuprizone diet (CD) for four weeks. Histology, immunofluorescence, Western blot and TUNEL assays were performed to evaluate the extent of demyelination and apoptosis in the hippocampus. Deletion of A₁ and A_2A AR alters spatial learning and memory. In A₁AR-/- mice, cuprizone feeding led to severe hippocampal demyelination, A_2AAR-/- mice had a significant increase in myelin whereas WT mice had intermediate demyelination. The A₁AR-/- CD-fed mice displayed significant astrocytosis and decreased expression of NeuN and MBP, whereas these proteins were increased in the A_2AAR-/- CD mice. Furthermore, Olig2 was upregulated in A₁AR-/- CD-fed mice compared to WT mice fed the standard diet. TUNEL staining of brain sections revealed a fivefold increase in the hippocampus of A₁AR-/- CD-fed mice. Also, WT mice fed CD showed a significant decrease expression of A₁ AR. A₁ and A_2A AR are involved in OPC/OL functions with opposing roles in myelin regulation in the hippocampus. Thus, the neuropathological findings seen in MS may be connected to the depletion of A₁ AR.